The Zinc Transporter Slc30a8/ZnT8 Is Required in a Subpopulation of Pancreatic α-Cells for Hypoglycemia-induced Glucagon Secretion
| Autor: | Christophe Magnan, Stéphanie Migrenne Li, Guy A. Rutter, Elisa A. Bellomo, Erwann Philippe, Alejandra Tomas, Pedro Luis Herrera, David J. Hodson, Antonia Solomou, Gargi Meur |
|---|---|
| Přispěvatelé: | Medical Research Council (MRC) |
| Rok vydání: | 2015 |
| Předmět: |
Biochemistry
0302 clinical medicine Glucose homeostasis ddc:576.5 Cation Transport Proteins IN-VIVO Cells Cultured 0303 health sciences geography.geographical_feature_category diabetes SLC30A8 digestive oral and skin physiology zinc Glucagon secretion 11 Medical And Health Sciences Islet 3. Good health secretion ISLETS Zinc Transporter 8 Female 03 Chemical Sciences Life Sciences & Biomedicine hormones hormone substitutes and hormone antagonists EXPRESSION endocrine system Biochemistry & Molecular Biology medicine.medical_specialty 030209 endocrinology & metabolism Biology Hypoglycemia INSULIN-SECRETION Glucagon 03 medical and health sciences BETA-CELLS Insulin resistance Internal medicine medicine Animals GENOME-WIDE ASSOCIATION Molecular Biology 030304 developmental biology RELEASE FREE CYTOSOLIC ZN2+ geography Science & Technology calcium Cell Biology 06 Biological Sciences medicine.disease RISK LOCI Mice Inbred C57BL Metabolism Glucose Endocrinology Glucagon-Secreting Cells biology.protein GLUCOSE-HOMEOSTASIS Insulin Resistance Gene Deletion |
| Zdroj: | Journal of Biological Chemistry, Vol. 290, No 35 (2015) pp. 21432-21442 The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| Popis: | Background: The role of the type 2 diabetes risk gene SLC30A8, encoding ZnT8, in the control of glucagon secretion is not clearly established. Results: Inactivation of ZnT8 in a subset of α-cells leads to increased glucagon secretion in vivo and in vitro. Conclusion: ZnT8 is involved in normal glucagon release. Significance: SLC30A8 diabetes risk alleles may influence glucagon secretion. SLC30A8 encodes a zinc transporter ZnT8 largely restricted to pancreatic islet β- and α-cells, and responsible for zinc accumulation into secretory granules. Although common SLC30A8 variants, believed to reduce ZnT8 activity, increase type 2 diabetes risk in humans, rare inactivating mutations are protective. To investigate the role of Slc30a8 in the control of glucagon secretion, Slc30a8 was inactivated selectively in α-cells by crossing mice with alleles floxed at exon 1 to animals expressing Cre recombinase under the pre-proglucagon promoter. Further crossing to Rosa26:tdRFP mice, and sorting of RFP+: glucagon+ cells from KO mice, revealed recombination in ∼30% of α-cells, of which ∼50% were ZnT8-negative (14 ± 1.8% of all α-cells). Although glucose and insulin tolerance were normal, female αZnT8KO mice required lower glucose infusion rates during hypoglycemic clamps and displayed enhanced glucagon release (p < 0.001) versus WT mice. Correspondingly, islets isolated from αZnT8KO mice secreted more glucagon at 1 mm glucose, but not 17 mm glucose, than WT controls (n = 5; p = 0.008). Although the expression of other ZnT family members was unchanged, cytoplasmic (n = 4 mice per genotype; p < 0.0001) and granular (n = 3, p < 0.01) free Zn2+ levels were significantly lower in KO α-cells versus control cells. In response to low glucose, the amplitude and frequency of intracellular Ca2+ increases were unchanged in α-cells of αZnT8KO KO mice. ZnT8 is thus important in a subset of α-cells for normal responses to hypoglycemia and acts via Ca2+-independent mechanisms. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|